Compositions and methods of treating muscle atrophy and myotonic dystrophy

Abstract

Disclosed herein are polynucleic acid molecules, pharmaceutical compositions, and methods for treating muscle atrophy or myotonic dystrophy.

What is claimed is: 
     
       1. A small interfering RNA (siRNA)-antibody conjugate comprising an anti-transferrin receptor antibody or antigen-binding fragment thereof conjugated to an siRNA that hybridizes to a target sequence of human Atrogin-1 mRNA and mediates RNA interference against the human Atrogin-1 mRNA preferentially in a muscle cell, wherein the siRNA comprises a guide strand and a passenger strand, and the guide strand comprises a sequence selected from SEQ ID NO: 318, SEQ ID NO: 321, SEQ ID NO: 325, SEQ ID NO: 327, SEQ ID NO:333, SEQ ID NO: 337, SEQ ID NO:339, SEQ ID NO:342, SEQ ID NO:344, SEQ ID NO: 346, SEQ ID NO:348, SEQ ID NO:350, SEQ ID NO:353, SEQ ID NO:358, SEQ ID NO:359, SEQ ID NO:361, SEQ ID NO:363, SEQ ID NO:365, SEQ ID NO:366 and SEQ ID NO: 368. 
     
     
       2. The siRNA-antibody conjugate of  claim 1 , wherein the siRNA comprises at least one 2′ modified nucleotide, at least one modified internucleotide linkage, or at least one inverted abasic moiety. 
     
     
       3. The siRNA-antibody conjugate of  claim 1 , wherein the anti-transferrin receptor antibody or antigen-binding fragment thereof binds to a transferrin receptor on the cell surface of the muscle cell. 
     
     
       4. The siRNA-antibody conjugate of  claim 1 , wherein the muscle cell is a skeletal muscle cell or a cardiac muscle cell. 
     
     
       5. The siRNA-antibody conjugate of  claim 1 , wherein the guide strand or the passenger strand is from about 19 to about 30 nucleotides in length. 
     
     
       6. The siRNA-antibody conjugate of  claim 1 , wherein the siRNA-antibody conjugate comprises a linker connecting the anti-transferrin receptor antibody or antigen-binding fragment thereof to the siRNA. 
     
     
       7. The siRNA-antibody conjugate of  claim 2 , wherein the at least one 2′ modified nucleotide:
 comprises 2′-O-methyl, 2′-O-methoxyethyl (2′-O-MOE), 2′-O-aminopropyl, 2′-deoxy, 2′-deoxy-2′-fluoro, 2′-O-aminopropyl (2′-O-AP), 2′-O-dimethylaminoethyl (2′-O-DMAOE), 2′-O-dimethylaminopropyl (2′-O-DMAP), 2′-O-dimethylaminoethyloxyethyl (2′-O-DMAEOE), or 2′-O-N-methylacetamido (2′-O-NMA) modified nucleotide; 
 comprises locked nucleic acid (LNA) or ethylene nucleic acid (ENA); or 
 comprises a combination thereof. 
 
     
     
       8. The siRNA-antibody conjugate of  claim 2 , wherein the at least one modified internucleotide linkage comprises a phosphorothioate linkage or a phosphorodithioate linkage. 
     
     
       9. The siRNA-antibody conjugate of  claim 2 , wherein the siRNA comprises 3 or more 2′ modified nucleotides selected from 2′-O-methyl and 2′-deoxy-2′-fluoro. 
     
     
       10. The siRNA-antibody conjugate of  claim 1 , wherein the siRNA-antibody conjugate has a drug/siRNA to antibody ratio of from about 1 to 11 about 4. 
     
     
       11. The siRNA-antibody conjugate of  claim 1 , wherein the siRNA comprises a 5′-terminal vinylphosphonate modified nucleotide. 
     
     
       12. The siRNA-antibody conjugate of  claim 1 , wherein the anti-transferrin receptor antibody or antigen-binding fragment thereof comprises a humanized antibody or antigen-binding fragment thereof, chimeric antibody or antigen-binding fragment thereof, monoclonal antibody or antigen-binding fragment thereof, monovalent Fab′, divalent Fab2, single-chain variable fragment (scFv), diabody, minibody, nanobody, single-domain antibody (sdAb), or camelid antibody or antigen-binding fragment thereof. 
     
     
       13. The siRNA-antibody conjugate of  claim 1 , wherein the siRNA-antibody conjugate is formulated for parenteral, oral, intranasal, buccal, rectal, or transdermal administration.